Neurostimulator involving stimulation strategies and process for using it

ABSTRACT

This is a neurostimulator that is configured to treat epilepsy and other neurological disorders using certain stimulation strategies, particularly changing various pulse parameters, during the imposition of a burst of those pulses. The invention includes the processes embodying those stimulation strategies.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.11/142,063, filed May 31, 2005, which is a divisional of U.S. patentapplication Ser. No. 09/543,264, filed Apr. 5, 2000, now U.S. Pat. No.6,944,501, issued Sep. 13, 2005, which are hereby incorporated byreference in their entirety.

FIELD OF THE INVENTION

This invention is to a neurostimulator, preferably implantable in thecranium, that is configured to treat epilepsy and other neurologicaldisorders using certain stimulation strategies, particularly changingvarious pulse parameters during the imposition of a burst of thosepulses. The invention also includes processes embodying thosestimulation strategies.

BACKGROUND OF THE INVENTION

Epileptic seizures are characterized by excessive or abnormallysynchronous neuronal activity. Neurologists recognize a wide variety ofseizures. Partial onset seizures begin in one part of the brain; generalonset seizures arise throughout the entire brain simultaneously. Whenpartial onset seizures progress to involve much of the brain, they aresaid to have “secondarily generalized.” Some seizures result in the lossof conscious awareness and are termed “complex” seizures. So-called“simple” seizures may involve other symptoms, but consciousness isunimpaired. Seizure symptoms may include sensory distortions,involuntary movements, or loss of muscle tone. The behavioral featuresof a seizure often reflect a function of the cortex where the abnormalelectrical activity is found.

Physicians have been able to treat epilepsy by resecting certain brainareas by surgery and by medication. Brain surgery is irreversible, andis ineffective or is associated with neural morbidity in a sizablepercentage of cases. Medication is the most prevalent treatment forepilepsy. It is effective in over half of patients, but in the reminderof the patients, the medication is either ineffective in controllingseizures, or the patients suffer from debilitating side effects. A morepromising method of treating patients having epileptic seizures is byelectrical stimulation of the brain.

Since the early 1970's, electrical brain stimulators have been usedwhich provide more or less constant stimulation, the stimulation largelybeing unrelated to detected electrical activity.

Electrical stimulation of the nervous system has been used to suppressseizures. A device is described in Cooper et al. for stimulation of thecerebellum. See, “The Effect of Chronic Stimulation of Cerebellar Cortexon Epilepsy and Man,” I. S. Cooper et al in The Cerebellum, Epilepsy andBehavior, Cooper, Riklan and Snyder Edition, Pleman Press, New York1974. Others have utilized devices which stimulated the centro mediannucleus of the thalamus. See, “Electrical Stimulation of the CentroMedian Thalamic Nucleous in Control of Seizures: Long Term Studies.” F.Valasco et al, Epilepsia, 36 (1): 63-71, 1995. Chaos Theory has beenused to apply stimulation to a seizure focus in vitro to abort theseizure. See, S. Schiff et al, “Controlling Chaos in the Brain,” Nature,Volume 370, Aug. 25, 1994.

As described in U.S. Pat. No. 6,016,449, an improved brain stimulator isimplanted in the cranium and has leads terminating with electrodes incontact with brain tissue.

Conventional neurostimulators use fixed rate trains of either monophasicor biphasic electrical pulses of a fixed amplitude to stimulate neuraltissue. Neurons in the immediate vicinity of the electrodes are inducedto fire (i.e. are recruited) by the electrical pulses thereby modifyingthe natural electrical activity in the brain. During an epileptic event,there is abnormal synchronization of neural activity in the brain. Thepresent invention improves upon the prior art by varying the timing,amplitude and/or duration of the pulses to more effectively disrupt thesynchronized activity. Furthermore, the subject invention analyzes theeffect on the brain of the electrical pulses, and decides how to modifythe burst parameters in a subsequent burst to most effectively terminatethe seizure.

Responsive stimulation, specifically electrical stimulation, that isapplied to the brain, has not yet been used to treat patients inlong-term studies. This is true even though there are algorithmssuitable for detection of the onset of an epileptic seizure. Forinstance, Qu et al provide an algorithm said to recognize patterns ofelectrical activity similar to those developed while recording an actualepileptic seizure. See, Qu et al., “A Seizure Warning System forLong-Term Epilepsy Monitoring, Neurology,” 1995; 45:2250-2254.Similarly, Osario, et al. have suggested an algorithm applied to signalsfrom intracranial electrodes with good results. See Osario, et al. “AMethod For Accurate Automated Real-Time Seizure Detection,” Epilepsia,Vol. 35, supplement 4, 1995.

As used herein, “epileptiform activity” refers to the manifestation onan EEG (cortical, depth, or scalp) of abnormal brain activity whetherassociated with clinical manifestations or not. “Stimulation” or“electrical stimulation” means the application of an electric field orelectric current to biological tissue.

The inventive device and related process:

-   -   1. have improved ability to terminate epileptiform activity.    -   2. are less likely to initiate epileptiform activity if        stimulation is accidentally delivered during a normal EEG.    -   3. are less likely to generalize ongoing epileptiform activity.    -   4. are safer since the current density required to affect a        larger amount of brain tissue is lower than that found in the        prior art.

None of the cited documents describes the inventive procedures anddevices described below.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A shows constant pulse-to-pulse intervals in prior art burst.

FIGS. 1B to 1E depict varying pulse-to-pulse intervals for a burstaccording to the inventive process.

FIG. 2A shows a prior art burst having a constant pulse amplitude.

FIGS. 2B and 2C depict varying pulse amplitudes for a burst according tothe inventive process.

FIG. 3A shows a typical prior art pulse.

FIG. 3B shows a pulse with a hyperpolarizing prepulse.

FIG. 4A shows a prior art burst having constant pulse widths.

FIGS. 4B and 4C depict varying pulse widths for a burst according to theinventive process.

FIGS. 5A, 5B, and 5C depict epileptiform activity in the brain.

FIG. 6 depicts variously a representative EEG of epileptiform activityand a selection of burst initiations done according to the inventionthat represent various stages of delay from peaks detected as shown inFIGS. 5A-5C.

FIGS. 7A to 7E depict examples of bursts with varying pulse parametersas might be applied to the FIG. 7A device.

FIG. 8 is a depiction of one variation of the inventive neurostimulatorhaving multiple electrodes.

DETAILED DESCRIPTION OF THE INVENTION

This invention recognizes the phenomenon that stimulation whichprecipitates epileptiform activity is promoting synchronized activity inthe brain; stimulation intended to terminate epileptiform activitydesynchronizes brain activity. Therefore different parameters forstimulation are better depending upon whether the burst is intended toprovoke or terminate seizures.

This invention uses various parameters to optimize stimulation todesynchronize the brain activity to terminate epileptiform activity:

Pulse-To-Pulse Interval Variation

In one variation for treating epilepsy, the pulse-to-pulse intervalwithin a burst is not fixed as in prior art devices. To betterdesynchronize neuronal activity, the pulse-to-pulse interval is variedas shown in FIG. 1. The pulse-to-pulse intervals are generally kept to arange of 3 to 300 msec, and may be varied randomly or changed in asystematic fashion, such as incrementing or decrementing the pulse topulse interval within a burst. In addition to providing a bettermodality for terminating epileptiform activity, a burst with a varyingpulse-to-pulse interval can be optimized to avoid inducing epileptiformactivity, or generalizing a local seizure while maintaining highefficacy in terminating seizures. Once the electrodes are placed nearthe epileptogenic focus in the brain, the physician can use bursts ofpulses both to initiate and to terminate epileptiform activity. Byvarying the burst parameters, it is possible to arrive at a parameterset that is effective at terminating epileptiform activity, but isineffective at initiating it. For the purposes of this patent, a burstmay be any number of pulses, typically in the range from 1 to 100.

The examples shown in FIGS. 1A to 1E depict burst durations ofapproximately 400 msec for illustrative purposes. Burst durations of 10msec to 2000 msec or even longer may all be effective in terminatingepileptiform activity. FIG. 1A shows a prior art fixed rate burst withthe pulse-to-pulse interval fixed at 20 msec. FIG. 1B shows arepresentative burst where the pulse-to-pulse interval is varied in arandom, pseudo-random, or fractal fashion within the burst. FIG. 1Cshows a burst where the pulse-to-pulse interval decrements within theburst. FIG. 1D shows a burst where the pulse-to-pulse interval firstdecrements and then increments within the burst. FIG. 1E shows a burstthat is made up of shorter bursts. In the variation shown in FIG. 1E,the pulse sequence within the shorter bursts, the shorter burstdurations, and the intervals between the shorter bursts may be varied asdescribed with respect to FIGS. 1B to 1D. Additional burst patterns maybe generated from the basic patterns described herein without departingfrom the scope of this invention.

Pulse Amplitude Variation

Another inventive method for desynchronizing brain activity andterminating epileptiform activity is by spatially desynchronizingactivity in the vicinity of the stimulation electrode. To accomplishthis, various individual pulse parameters within a burst are varied forat least a portion of the burst. Specifically, by varying the amplitudeof the pulses, individual pulses may be tailored to directly depolarizedifferent neural tissue. Lower amplitude pulses directly depolarizetissue in the immediate vicinity of the electrode; higher amplitudepulses directly depolarize tissue both near the electrode and at somedistance from the electrode. By varying the amplitude of the pulseswithin a burst, local tissue is depolarized at a higher rate than tissuesomewhat distant from the electrode. The spatial heterogeneity of thetiming of depolarization around the electrode is more effective indesynchronizing brain activity than prior art pulse regimes.

In FIG. 2A to 2C, the fixed rate bursts are depicted with durations ofapproximately 400 msec for illustrative purposes only. FIG. 2A shows anexample of a prior art, fixed amplitude burst. FIG. 2B shows a bursthaving a systematic variation of pulse amplitude within the burst. FIG.2C shows a burst where the pulse amplitude within the burst varies in arandom, pseudo-random, or fractal fashion.

Hyperpolarizing Prepulse

A variation of the inventive technique is to include a hyperpolarizingprepulse to render tissue near the electrode less sensitive than tissueat some distance from the electrode. This allows more independentcontrol of the sequence of depolarization of tissue near and more distalto the electrode. FIG. 3A shows a typical prior art pulse having astimulating phase 301 and a charge balance phase 302 of equal duration.Typical phase durations vary from 40 to 500 microseconds. FIG. 3B showsa pulse having a hyperpolarizing prephase 303 followed by a stimulatingphase 304. The prephase 303 is typically of low amplitude and longerduration, and would not stimulate tissue effectively if used on its own.The stimulating phase 304 is of higher amplitude and its duration may beadjusted to charge balance the hyperpolarizing prephase 304. The pulsedescribed in FIG. 3B maybe used selectively or throughout thestimulation strategies discussed in conjunction with the inventivevariations found above.

Pulse Width Variation

In addition to varying the pulse amplitude, it is advantageous also tovary the pulse width of individual pulses within a burst. Shorter pulses(on the order of 50 to 150 microseconds) tend to directly depolarizesmaller diameter nerve cells. Longer pulses (100 to 500 microseconds)depolarize larger diameter nerve cells. By varying the pulse width ofthe pulses within a burst, it is possible to preferentially depolarizelarger nerves with some of the pulses and smaller nerves with otherpulses. The result is a greater spatial variation of the distribution ofstimulated nerves on a pulse by pulse basis which results in greaterefficacy in desynchronizing brain activity thereby terminatingepileptiform activity.

In FIGS. 4A to 4C, the number of pulses within the bursts is fewer thanin previous examples, and the width of the pulses within the bursts isexaggerated for clarity. FIG. 4A shows a typical prior art burst wherethe pulse widths of the pulses within the burst are all the same. FIG.4B is an example of a burst where the pulse widths are varied insystematic fashion. FIG. 4C is an example of a burst where the pulsewidths are varied in a random, pseudo-random or fractal fashion.

Since the tissue disposed near an electrode may have highly variableanatomy, it is anticipated that all of the parameters described abovewith regard to the Figures (e.g., pulse to pulse interval, pulseamplitude, the use of hyperpolarizing pulses, and pulse width) may bevaried alone or in combination to optimize the ability of a burst toterminate epileptiform activity in the brain while improving the safetyof the burst by reducing the likelihood of inducing epileptiformactivity or generalizing such pre-existing activity.

EEG-Based Stimulation—Pulse-To Pulse Interval

In addition to producing bursts that contain intervals that are set inabsolute time increments, this invention provides the improvement ofsetting pulse-to-pulse interval based upon the detected interval of theepileptiform activity as sensed on the electrodes in contact with thebrain. In this mode of operation, the rate of the sensed epileptiformactivity is detected and measured. The rate of the detected activity maybe used to determine specific pulse-to-pulse intervals or averagepulse-to-pulse intervals of the burst used to terminate the epileptiformactivity.

FIG. 5A to 5C illustrate a method for generating a burst where some orall of the pulse-to-pulse intervals are based upon the rate of theepileptiform activity. FIGS. 5A, 5B, and 5C show typical examples ofepileptiform activity detected from electrodes in contact with thecortex near the epileptogenic region of a brain. The first step is todetermine the rate or average rate of the epileptiform activity. Bydetecting the peaks of the epileptiform activity, and counting (forexample) four intervals, and dividing the result by four, the averageinterval, I_(avg), may be determined. Peak detection and intervalmeasurement is well known in the art of automated EEG analysis. See, forinstance, “Automatic Detection of Seizures and Spikes” Jean Gotman,Journal of Clinical Neurophysiology, 16(2):13-140, 1999 and U.S. patentapplication Ser. No. 09/517,797, filed Mar. 2, 2000, entitled“Neurological Event Detection Using Processed Display Channel BasedAlgorithms and Devices Incorporating These Procedures”, the entirety ofwhich are incorporated by reference.

Peak markers 501, 503, and 505 in FIGS. 5A, 5B, and 5C respectivelydelineate four intervals of each of the epileptiform examples. Themeasurements X, Y, and Z shown by 502, 504 and 506 in FIGS. 5A, 5B and5C respectively are divided by four to give the I_(avg) in each case. Itmay be desirable to use more or less intervals in calculating theinterval average, or the mode or some other mathematical means may beused without departing from the intention of this invention.

Once the I_(avg) has been determined, it may be used in my inventiveprocess to set pulse-to-pulse intervals within a burst. For example inFIG. 1A, the pulse-to-pulse interval in the fixed rate burst may bedetermined by taking a percentage of the measured I_(avg). The followingtable of derived pulse-to-pulse intervals for a burst provides a numberof calculated percentages, the use of which will be apparent just below:

Measured I_(avg) (msec) Percent 60 80 120 10%  6  8 12 20% 12 16 24 30%18 24 36

As can be seen, for a given programmed setting of percentage, thepulse-to-pulse interval of the burst varies to accommodate differentepileptiform waveforms. This provides an advantage over prior art fixedrate intervals in terminating epileptiform activity.

To apply the same principle to the burst of 1B, the averagepulse-to-pulse interval may then be set to be equal to a percentage ofthe measured I_(avg). For FIGS. 1C and 1D, the initial interval may beset equal to or set to a percentage of the measured I_(avg). Subsequentintervals may then be calculated by adding or subtracting a fixed valueor percentage from the previous interval. The pulse-to-pulse intervalsshown in FIG. 1E may calculated in the same manner as those of theprevious examples.

The range of percentages used may be from 5% to 300% of the measuredI_(avg) depending on the application, and the patient's condition.

EEG-Based Stimulation—Synchronization/Delay

To further improve the efficacy of a burst in terminating epileptiformactivity, the subject invention also provides for synchronization of theburst with the EEG (FIG. 6). To do this, a timing signal is generatedoff of the sensed EEG. A delay that varies from 0 to 100% of thedetected EEG interval is initiated from the timing signal and is used totrigger the start of the burst. Graph 180 shows a representative EEG ofepileptiform activity. Stimulation 182 shows a burst delivered with a 0%delay, that is simultaneous with a spike on the EEG. Stimulation 184shows a representative burst having a 50% delay; and Stimulation 186depicts a burst having a 75% delay. The synchronization techniquedescribed with regard to FIG. 6 may be used in conjunction with theadaptive pulse-to-pulse interval as described in conjunction with FIGS.5A to 5C in that a minimal number of pulses may be used in a burst, insome cases as few as one, but more typically three or four. Byminimizing the number of pulses, a burst which is effective interminating epileptiform activity is safer as it is less likely toprovoke a seizure if accidentally applied.

A further method of synchronizing a burst is to trigger the first pulseof the burst selectively on a positive peak, a negative peak, or someother feature of the EEG signal. The detected EEG is preferentially froman electrode near or on the epileptogenic focus, but different featuresmay be used to optimize the synchronization of the burst depending uponwhere the electrode is relative to the epileptogenic activity in thebrain, and the patient's condition.

EEG-Based Stimulation—Detection and Repetition

After the burst is delivered, the EEG is re-examined, and if theepileptiform activity was not terminated, a subsequent burst isdelivered. The subsequent burst may have the same parameters as thefirst burst, may re-adapt to the changing EEG rate, or may have newparameters to more aggressively attempt to terminate the epileptiformactivity (e.g. higher rate, more pulses, higher output, or modifiedpulse-to-pulse intervals).

Spatially-Determined Stimulation

One important aspect of this invention is the potential use of multiplebrain contact electrodes to provide therapy. One embodiment of a deviceespecially suitable for practicing certain variations of the inventiveprocess is shown in FIG. 7A. The FIG. 7A includes multiple electrodes701, 702, 703, and 704, to enhance the ability of electrical stimulationto desynchronize brain activity to terminate epileptiform activity.Although the same burst may be delivered from a multiplicity ofelectrodes in the vicinity of the epileptogenic focus, it is preferableto provide bursts having different parameters, particularlypulse-to-pulse timing, to achieve a greater degree of spatialheterogeneity of neural activity and thereby most effectivelydesynchronize brain activity. This method for terminating epileptiformactivity provides additional benefits in that lower current densities atthe electrodes may be used to affect a larger amount of brain tissuethan if a single electrode were used. Lower current densities areassociated with fewer histological changes in the vicinity of thestimulating electrodes. Furthermore, the use of different burstparameters and/or lower current densities from a number of electrodes isless likely to initiate epileptiform activity or generalize on-goingepileptiform activity.

FIG. 7A depicts a representative electrode assembly placed under thedura mater on the brain, and viewed from above. There are fourelectrodes 701, 702, 703 and 704 in an insulated electrode backing 705that prevents current flow back to the dura mater. Current flow back tothe dura matter is often uncomfortable for the patient. The electrodesare electrically connected to the neurostimulator (not shown) by wiresenclosed in the lead body 706. The epileptogenic region 707 is outlinedfor clarity, but is generally not visually apparent. To achieve spatialheterogeneity of electrical stimulation to most optimally desynchronizeneuronal activity, the strategies described in this patent may beapplied to all the electrodes 701-704 together or separately. FIGS. 7B,7C, 7D, and 7E show an example of separate burst parameters beingapplied to electrodes 701, 702, 703 and 704 respectively todesynchronize neuronal activity in a wide area of brain tissue near theepileptogenic focus.

Implantable Neurostimulator

The inventive device includes a neurostimulator central unit and atleast one electrode. The neurostimulator central unit includes thenecessary circuitry, e.g., A/D converters, filters, central processingunit(s), digital processing circuits, blanking circuits, power supplies,batteries, signal generators, etc., and programming configured andadapted to perform the inventive steps listed above. Specifically theneurostimulator central unit (800) desirably is as shown in FIG. 8 andis shaped in such a way that it conforms to the shape of the skull,although it need not be so. The neurostimulator central unit should atleast contain an electrical stimulation source and preferably devicesfor detecting epileptiform activity and for initiating and for varyingthe responsive electrical stimulation as described above. Theneurostimulator assembly should also include at least a first brainelectrical activity sensor (802) and a responsive electricalneurostimulator electrode (804), preferably in the form shown in FIG.7A. The various necessary connectors, leads, and supporting componentsare also included.

A highly desirable aspect of the inventive device is the use of multiplebrain electrodes to provide therapy. The measuring electrodes arepreferable in contact with the brain, but, as discussed above, may bescalp electrodes or within the brain tissue. Multiple electrodes enhancethe ability of electrical stimulation to desynchronize brain activity interminating epileptiform activity. Although the same burst may bedelivered from a multiplicity of electrodes in the vicinity of theepileptogenic focus, as noted above, preferable to introduce burstshaving different signal parameters, particularly pulse-to-pulse timing,to the brain to achieve a greater degree of spatial heterogeneity ofneural activity and most effectively desynchronize brain activity.

The application of multiple electrodes to different parts or regions ofthe brain also provide a way to treat epilepsy having more than onefocus. Electrodes are placed on or near the various epileptogenic foci.The inventive neurostimulator may sense and stimulate independently fromeach electrode. Optional amplifier blanking eliminates cross talk, andlogical flow in the device's software keeps the device from erroneouslydetecting its own output as epileptiform activity.

This inventive device may utilize independently actuatable, spatiallyseparated electrodes so that those epilepsies having many epileptogenicfoci or for which the focus is so diffuse the seizure arises from alarge portion of the brain, may be treated. In such a case, it isdesirable to place one electrode deep in the brain, preferably in thearea of the hippocampus. Additional electrodes may be placed on thesurface of the cortex. When epileptiform activity is detected, thedevice stimulates from the hippocampal region to take advantage of thelarge number of neural pathways emanating from that area into thecortex. Electrodes on the cortex provide additional electrical access tothe brain allowing electrical stimulation to terminate epileptiformactivity having a greater spatial extent.

Although preferred embodiments of the invention have been describedherein, it will be recognized that a variety of changes andmodifications can be made without departing from the spirit of theinvention as found in the appended claims.

I claim as my invention:
 1. A method for treating an abnormalneurological condition comprising: detecting electrical activity ofbrain tissue wherein the detected electrical activity is characterizedby at least one detected parameter; applying a plurality of bursts ofelectrical stimulation to the brain tissue, wherein each burst of theplurality of bursts comprises a determined number of electrical pulsesbeing characterizable by a plurality of burst parameters; and varying atleast one of the burst parameters during at least a portion of the timethe plurality of bursts of electrical stimulation is applied to vary thebursts so that the burst parameters of at least one burst of theplurality of bursts are different from the burst parameters of at leastone other burst of the plurality of bursts, wherein the varying is basedon a timing of the at least one detected parameter.
 2. The method ofclaim 1 further including varying at least one of the burst parametersbased on the timing of the at least one detected parameter relative to atiming of an application of the at least one burst of the plurality ofbursts.
 3. The method of claim 1 wherein the at least one detectedparameter is a pulse-to-pulse interval and the method further includesvarying at least one of the burst parameters of the plurality of burstparameters based on the detected pulse-to-pulse interval.
 4. A methodfor treating an abnormal neurological condition comprising: detectingelectrical activity of brain tissue wherein the detected electricalactivity is characterized by at least one detected parameter; applying aplurality of bursts of electrical stimulation to the brain tissue,wherein each burst of the plurality of bursts comprises a determinednumber of electrical pulses being characterizable by a plurality ofburst parameters and at least one burst of the plurality of bursts isapplied at a time that is synchronized to a time at which the at leastone detected parameter is detected; and varying at least one of theburst parameters during at least a portion of the time the plurality ofburst parameters of electrical stimulation is applied to vary the burstsso that the burst parameters of at least one burst of the plurality ofbursts are different from the burst parameters of at least one otherburst of the plurality of bursts.
 5. A method for treating an abnormalneurological condition comprising: detecting a rate of electricalactivity in signals sensed from brain tissue; identifying an intervalcorresponding to the detected rate; applying a plurality of bursts ofelectrical stimulation to the brain tissue, wherein each burst of theplurality of bursts comprises a determined number of electrical pulsesbeing characterizable by a plurality of burst parameters and at leastone burst of the plurality of bursts is applied based on detection ofthe interval; and varying at least one of the burst parameters during atleast a portion of a time the plurality of bursts of electricalstimulation is applied to vary the bursts so that the burst parametersof at least one burst of the plurality of bursts are different from theburst parameters of at least one other burst of the plurality of bursts.